Compounds for the Treatment Of Acute and Chronic Kidney Disease

ABSTRACT

The present disclosure is concerned with biaryl aminomaleimide compounds for the treatment of disorders associated with heme oxygenase-1 (HO-1) signaling dysfunction such as, for example, kidney diseases (e.g., chronic kidney disease, acute kidney injury). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/115,421, filed on Nov. 18, 2020, the contents of which isincorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING

The Sequence Listing submitted Nov. 17, 2021 as a text file named“19044_0451U2_ST25.txt,” created on Nov. 5, 2021, and having a size of8,192 bytes is hereby incorporated by reference pursuant to 37 C.F.R. §1.52(e)(5).

BACKGROUND

Acute kidney injury (AKI) is a major cause for morbidity and mortalityin hospitalized patients, developing in about 5-7% of patients andimpairing recovery of about 15-25% of intensive care unit (ICU)patients. Despite major advances in renal replacement therapy, themortality in patients with AKI remains largely unchanged and can be ashigh as 80% in ICU patients. Additionally, AKI is now linked to thesubsequent development of chronic kidney disease (CKD). Numeroustherapeutic interventions have been evaluated in clinical trials, withnone proven successful. General supportive care and dialysis remain theprimary treatment modalities. Thus, there remains a need for compoundsand compositions for treating kidney diseases, and methods of making andusing same.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompounds and compositions for use in the prevention and treatment ofdisorders associated with heme oxygenase-1 (HO-1) signaling such as, forexample, kidney diseases including, but not limited to, chronic kidneydisease and acute kidney injury.

Thus, disclosed are compounds having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3e), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

Also disclosed are methods for treating a disorder associated with hemeoxygenase-1 (HO-1) signaling dysfunction in a subject in need thereof,the method comprising administering to the subject an effective amountof a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby treating the disorderin the subject.

Also disclosed are methods for modifying HO-1 signaling in a subject,the method comprising administering to the subject an effective amountof a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3e), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

Also disclosed are methods for modifying HO-1 signaling in a cell, themethod comprising contacting the cell with an effective amount of acompound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3e), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the cell.

Also disclosed are kits comprising a compound having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, and one or more of: (a) anagent associated with the treatment of a disorder associated with HO-1signaling dysfunction; (b) instructions for administering the compoundin connection with treating a disorder associated with HO-1 signalingdysfunction; and (c) instructions for treating a disorder associatedwith HO-1 signaling dysfunction.

Also disclosed are compounds having a structure:

or a pharmaceutically acceptable salt thereof.

Also disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a disclosed compound and apharmaceutically acceptable carrier.

Also disclosed are methods for treating a disorder associated with HO-1signaling dysfunction in a subject in need thereof, the methodcomprising administering to the subject an effective amount of adisclosed compound, thereby treating the disorder.

Also disclosed are methods for modifying HO-1 signaling in a subject,the method comprising administering to the subject an effective amountof a disclosed compound, thereby modifying HO-1 signaling in thesubject.

Also disclosed are methods for modifying HO-1 signaling in a cell, themethod comprising contacting the cell with an effective amount of adisclosed compound, thereby modifying HO-1 signaling in the cell.

Also disclosed are kits comprising a disclosed compound, and one or moreof: (a) an agent associated with the treatment of a disorder associatedwith HO-1 signaling dysfunction; (b) instructions for administering thecompound in connection with treating a disorder associated with HO-1signaling dysfunction; and (c) instructions for treating a disorderassociated with HO-1 signaling dysfunction.

Also disclosed are methods of identifying a compound that modulates hemeoxygenase-1 (HO-1) signaling, the method comprising: (a) contacting acell with a candidate compound, wherein the cell comprises: (i) a vectorcomprising: (1) a promoter operably linked to a nucleic acid comprisingthe sequence of NCBI Accession No. Z82244; (2) an enhancer, wherein theenhancer comprises the sequence of SEQ ID NO: 1; and (3) a selectablemarker; or (ii) a vector comprising: (1) a promoter operably linked to anucleic acid comprising a triple mutant of the sequence of NCBIAccession No. Z82244; and (2) a selectable marker; wherein the vectorexpresses HO-1 or a mutant thereof, (b) determining expression of theselectable marker in the cell; and (c) identifying the candidatecompound as a compound that modulates HO-1 signaling when expression ofthe selectable marker is modulated in the cell.

Also disclosed are compounds that modulate heme oxygenase-1 (HO-1)identified by a disclosed method.

Also disclosed are method of increasing heme oxygenase-1 (HO-1)signaling in a subject, the method comprising administering a compoundthat increases HO-1 signaling, wherein the ability of the compound toincrease HO-1 signaling is determined by: (a) contacting a cell with acandidate compound, wherein the cell comprises: (i) a vector comprising:(1) a promoter operably linked to a nucleic acid comprising the sequenceof NCBI accession no. Z82244; (2) an enhancer, wherein the enhancercomprises the sequence of SEQ ID NO: 1; and (3) a selectable marker; or(ii) a vector comprising: (1) a promoter operably linked to a nucleicacid comprising a triple mutant of the sequence of NCBI accession no.Z82244; and (2) a selectable marker; wherein the vector expresses HO-1or a mutant thereof, (b) determining expression of the selectable markerin the cell; and (c) identifying the candidate compound as a compoundthat that increases HO-1 signaling when expression of the selectablemarker is increased in the cell.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a representative schematic of a pHOGL3/4.5+220 constuct.

FIG. 2 shows a representative schematic of a pHOGL3/Triple Mutantconstruct.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. DEFINITIONS

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated ±10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, “IC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50%inhibition of a biological process, or component of a process, includinga protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, anIC₅₀ can refer to the concentration of a substance that is required for50% inhibition in vivo, as further defined elsewhere herein. In afurther aspect, IC₅₀ refers to the half-maximal (50%) inhibitoryconcentration (IC) of a substance.

As used herein, “EC₅₀” is intended to refer to the concentration of asubstance (e.g., a compound or a drug) that is required for 50% agonismof a biological process, or component of a process, including a protein,subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC₅₀ canrefer to the concentration of a substance that is required for 50%agonism in vivo, as further defined elsewhere herein. In a furtheraspect, EC₅₀ refers to the concentration of agonist that provokes aresponse halfway between the baseline and maximum response.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal. A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage forms can comprise inventive a disclosed compound, aproduct of a disclosed method of making, or a salt, solvate, orpolymorph thereof, in combination with a pharmaceutically acceptableexcipient, such as a preservative, buffer, saline, or phosphate bufferedsaline. Dosage forms can be made using conventional pharmaceuticalmanufacturing and compounding techniques. Dosage forms can compriseinorganic or organic buffers (e.g., sodium or potassium salts ofphosphate, carbonate, acetate, or citrate) and pH adjustment agents(e.g., hydrochloric acid, sodium or potassium hydroxide, salts ofcitrate or acetate, amino acids and their salts) antioxidants (e.g.,ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20,polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate),solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol,trehalose), osmotic adjustment agents (e.g., salts or sugars),antibacterial agents (e.g., benzoic acid, phenol, gentamicin),antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g.,thimerosal, 2-phenoxyethanol, EDTA), polymeric stabilizers andviscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the term “therapeutic agent” includes any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14^(th) edition), thePhysicians' Desk Reference (64^(th) edition), and The PharmacologicalBasis of Therapeutics (12^(th) edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;anti-cancer and anti-neoplastic agents such as kinase inhibitors, polyADP ribose polymerase (PARP) inhibitors and other DNA damage responsemodifiers, epigenetic agents such as bromodomain and extra-terminal(BET) inhibitors, histone deacetylase (HDAc) inhibitors, iron chelatorsand other ribonucleotides reductase inhibitors, proteasome inhibitorsand Nedd8-activating enzyme (NAE) inhibitors, mammalian target ofrapamycin (mTOR) inhibitors, traditional cytotoxic agents such aspaclitaxel, dox, irinotecan, and platinum compounds, immune checkpointblockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4)monoclonal antibody (mAB), programmed cell death protein 1(PD-1)/programmed cell death-ligand 1 (PD-L1) mAB, cluster ofdifferentiation 47 (CD47) mAB, toll-like receptor (TLR) agonists andother immune modifiers, cell therapeutics such as chimeric antigenreceptor T-cell (CAR-T)/chimeric antigen receptor natural killer(CAR-NK) cells, and proteins such as interferons (IFNs), interleukins(ILs), and mAbs; anti-ALS agents such as entry inhibitors, fusioninhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs),nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reversetranscriptase inhibitors, NCP7 inhibitors, protease inhibitors, andintegrase inhibitors; analgesics and analgesic combinations, anorexics,anti-inflammatory agents, anti-epileptics, local and generalanesthetics, hypnotics, sedatives, antipsychotic agents, neurolepticagents, antidepressants, anxiolytics, antagonists, neuron blockingagents, anticholinergic and cholinomimetic agents, antimuscarinic andmuscarinic agents, antiadrenergics, antiarrhythmics, antihypertensiveagents, hormones, and nutrients, antiarthritics, antiasthmatic agents,anticonvulsants, antihistamines, antinauseants, antineoplastics,antipruritics, antipyretics; antispasmodics, cardiovascular preparations(including calcium channel blockers, beta-blockers, beta-agonists andantiarrythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

As used herein, “modulate,” “modulating,” and “modulation” mean a changein activity or function or number. The change may be an increase or adecrease, an enhancement or an inhibition of the activity, function, ornumber.

The terms “alter” or “modulate” can be used interchangeably herein. Whenused in reference to, for example, the expression of a nucleotidesequence in a cell, “alter” or “modulate” means that the level ofexpression of the nucleotide sequence in a cell after applying a methodas described herein is different from its expression in the cell beforeapplying the method.

As used herein, a “candidate compound” can be a compound suspected tomodulate HO-1 signaling.

The term “vector” or “construct” refers to a nucleic acid sequencecapable of transporting into a cell another nucleic acid to which thevector sequence has been linked. The term “expression vector” includesany vector, (e.g., a plasmid, cosmid, or phage chromosome) containing agene construct in a form suitable for expression by a cell (e.g., linkedto a transcriptional control element). “Plasmid” and “vector” are usedinterchangeably, as a plasmid is a commonly used form of vector.Moreover, the invention is intended to include other vectors that serveequivalent functions.

The term “expression vector” is used herein to refer to vectors that arecapable of directing the expression of genes to which they areoperatively-linked. Common expression vectors of utility in recombinantDNA techniques are often in the form of plasmids. Recombinant expressionvectors can comprise a nucleic acid as disclosed herein in a formsuitable for expression of the acid in a host cell. In other words, therecombinant expression vectors can include one or more regulatoryelements or promoters, which can be selected based on the host cellsused for expression that is operatively linked to the nucleic acidsequence to be expressed.

The term “operatively linked to” refers to the functional relationshipof a nucleic acid with another nucleic acid sequence. Promoters,enhancers, transcriptional and translational stop sites, and othersignal sequences are examples of nucleic acid sequences operativelylinked to other sequences. For example, operative linkage of DNA to atranscriptional control element refers to the physical and functionalrelationship between the DNA and promoter such that the transcription ofsuch DNA is initiated from the promoter by an RNA polymerase thatspecifically recognizes, binds to and transcribes the DNA.

As used herein, the terms “promoter,” “promoter element,” or “promotersequence” are equivalents and, as used herein, refer to a DNA sequencethat when operatively linked to a nucleotide sequence of interest iscapable of controlling the transcription of the nucleotide sequence ofinterest into mRNA. A promoter is typically, though not necessarily,located 5′ (i.e., upstream) of a nucleotide sequence of interest (e.g.,proximal to the transcriptional start site of a structural gene) whosetranscription into mRNA it controls, and provides a site for specificbinding by RNA polymerase and other transcription factors for initiationof transcription.

Suitable promoters can be derived from genes of the host cells whereexpression should occur or from pathogens for this host cells (e.g.,tissue promoters or pathogens like viruses). If a promoter is aninducible promoter, then the rate of transcription increases in responseto an inducing agent. In contrast, the rate of transcription is notregulated by an inducing agent if the promoter is a constitutivepromoter. Also, the promoter may be regulated in a tissue-specific ortissue preferred manner such that it is only active in transcribing theassociated coding region in a specific tissue type(s) such as leaves,roots, or meristem. The term “tissue specific,” as it applies to apromoter, refers to a promoter that is capable of directing selectiveexpression of a nucleotide sequence or gene of interest to a specifictype of tissue in the relative absence of expression of the samenucleotide sequence or gene of interest in a different type of tissue.

Disclosed herein are vectors comprising any of the nucleic acidconstructs described herein. Vectors comprising nucleic acids orpolynucleotides as described herein are also provided. As used herein, a“vector” refers a carrier molecule into which another DNA segment can beinserted to initiate replication of the inserted segment. A nucleic acidsequence can be “exogenous,” which means that it is foreign to the cellinto which the vector is being introduced or that the sequence ishomologous to a sequence in the cell but in a position within the hostcell nucleic acid in which the sequence is ordinarily not found. Vectorsinclude plasmids, cosmids, and viruses (e.g., bacteriophage, animalviruses, and plant viruses), and artificial chromosomes (e.g., YACs).Vectors can comprise targeting molecules. A targeting molecule is onethat directs the desired nucleic acid to a particular organ, tissue,cell, or other location in a subject's body. A vector, generally, bringsabout replication when it is associated with the proper control elements(e.g., a promoter, a stop codon, and a polyadenylation signal). Examplesof vectors that are routinely used in the art include plasmids andviruses. The term “vector” includes expression vectors and refers to avector containing a nucleic acid sequence coding for at least part of agene product capable of being transcribed. A variety of ways can be usedto introduce an expression vector into cells. In some aspects, theexpression vector comprises a virus or an engineered vector derived froma viral genome. As used herein, “expression vector” is a vector thatincludes a regulatory region. A variety of host/expression vectorcombinations can be used to express the nucleic acid sequences disclosedherein. Examples of expression vectors include but are not limited toplasmids and viral vectors derived from, for example, bacteriophages,retroviruses (e.g., lentiviruses), and other viruses (e.g.,adenoviruses, poxviruses, herpesviruses, and adeno-associated viruses).Vectors and expression systems are commercially available and known toone skilled in the art.

The vectors disclosed herein can also include detectable label orselectable marker. Such detectable labels or selectable marker caninclude a tag sequence designed for detection (e.g., purification orlocalization) of an expressed polypeptide or polynucleotide. Tagsequences include, for example, fluorescent fusion protein, glutathioneS-transferase, polyhistidine, c-myc, hemagglutinin, or Flag™ tag, andcan be fused with a polynucleotide encoding a polypeptide, an encodedpolypeptide or can be inserted anywhere within the polypeptide,including at either the carboxyl or amino terminus.

Detection of the tagged molecule can be achieved using a number ofdifferent techniques. Examples of such techniques include:immunohistochemistry, immunoprecipitation, flow cytometry,immunofluorescence microscopy, ELISA, immunoblotting (“Westernblotting”), and affinity chromatography. Epitope tags add a knownepitope (e.g., antibody binding site) on the subject protein, to providebinding of a known and often high-affinity antibody, and therebyallowing one to specifically identify and track the tagged protein thathas been added to a living organism or to cultured cells. Examples ofepitope tags include, but are not limited to, myc, T7, GST, GFP, HA(hemagglutinin), V5, and FLAG tags.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms. The term alkyl group can also bea C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6alkyl, C1-C7 alkyl, CT-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the likeup to and including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹—OA² or—OA¹-(OA²)_(a)—OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbomenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen,” or “halide” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and“polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine,furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole,thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine,including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-CT 1 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon-containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

When the disclosed compounds contain one chiral center, the compoundsexist in two enantiomeric forms. Unless specifically stated to thecontrary, a disclosed compound includes both enantiomers and mixtures ofenantiomers, such as the specific 50:50 mixture referred to as a racemicmixture. The enantiomers can be resolved by methods known to thoseskilled in the art, such as formation of diastereoisomeric salts whichmay be separated, for example, by crystallization (see, CRC Handbook ofOptical Resolutions via Diastereomeric Salt Formation by David Kozma(CRC Press, 2001)); formation of diastereoisomeric derivatives orcomplexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step can liberate the desired enantiomeric form. Alternatively,specific enantiomers can be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon in adisclosed compound is understood to mean that the designatedenantiomeric form of the compounds can be provided in enantiomericexcess (e.e.). Enantiomeric excess, as used herein, is the presence of aparticular enantiomer at greater than 50%, for example, greater than60%, greater than 70%, greater than 75%, greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 98%, or greaterthan 99%. In one aspect, the designated enantiomer is substantially freefrom the other enantiomer. For example, the “R” forms of the compoundscan be substantially free from the “S” forms of the compounds and are,thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms ofthe compounds can be substantially free of “R” forms of the compoundsand are, thus, in enantiomeric excess of the “R” forms.

When a disclosed compound has two or more chiral carbons, it can havemore than two optical isomers and can exist in diastereoisomeric forms.For example, when there are two chiral carbons, the compound can have upto four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and(R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirrorimage stereoisomers of one another. The stereoisomers that are notmirror-images (e.g., (S,S) and (R,S)) are diastereomers. Thediastereoisomeric pairs can be separated by methods known to thoseskilled in the art, for example chromatography or crystallization, andthe individual enantiomers within each pair may be separated asdescribed above. Unless otherwise specifically excluded, a disclosedcompound includes each diastereoisomer of such compounds and mixturesthereof.

The compounds according to this disclosure may form prodrugs at hydroxylor amino functionalities using alkoxy, amino acids, etc., groups as theprodrug forming moieties. For instance, the hydroxymethyl position mayform mono-, di-, or triphosphates and again these phosphates can formprodrugs. Preparations of such prodrug derivatives are discussed invarious literature sources (examples are: Alexander et al., J. Med.Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).The nitrogen function converted in preparing these derivatives is one(or more) of the nitrogen atoms of a compound of the disclosure.

“Derivatives” of the compounds disclosed herein are pharmaceuticallyacceptable salts, prodrugs, deuterated forms, radio-actively labeledforms, isomers, solvates and combinations thereof. The “combinations”mentioned in this context refer to derivatives falling within at leasttwo of the groups: pharmaceutically acceptable salts, prodrugs,deuterated forms, radio-actively labeled forms, isomers, and solvates.Examples of radio-actively labeled forms include compounds labeled withtritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and thelike.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as 3H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., 3H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids, which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Strem Chemicals (Newburyport, Mass.),Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or areprepared by methods known to those skilled in the art followingprocedures set forth in references such as Fieser and Fieser's Reagentsfor Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd'sChemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes(Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40(John Wiley and Sons, 1991); March's Advanced Organic Chemistry, (JohnWiley and Sons, 4th Edition); and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compounds and compositions disclosed hereinhave certain functions. Disclosed herein are certain structuralrequirements for performing the disclosed functions, and it isunderstood that there are a variety of structures that can perform thesame function that are related to the disclosed structures, and thatthese structures will typically achieve the same result.

B. BIARYL AMINOMALEIMIDES

In one aspect, the invention relates to biaryl aminomaleimides useful inpreventing and treating disorders associated with heme oxygenase-1(HO-1) signaling such as, for example, kidney diseases including, butnot limited to, chronic kidney disease and acute kidney injury.

In one aspect, the compounds of the invention are useful in thetreatment of kidney diseases, as further described herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof.

In one aspect, disclosed are compounds having a structure:

or a pharmaceutically acceptable salt thereof.

In various aspects, the compound has a structure represented by aformula:

In various aspects, the compound has a structure represented by aformula:

In various aspects, the compound has a structure represented by aformula:

In various aspects, the compound has a structure represented by aformula:

In various aspects, the compound has a structure represented by aformula:

In various aspects, when one or two of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at least two ofR^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups.

In various aspects, when one or two of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is —OH or C1-C4 alkoxy and at least one of the remainingR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups is a differentnon-hydrogen group, then at least one of R^(3a), R^(3b), R^(3c), andR^(3d) are non-hydrogen groups.

In various aspects, when one of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is C1-C4 hydroxyalkyl, then at least one of R^(1a), R^(1b),R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), and R^(3d) is anon-hydrogen group.

In various aspects, the compound is not:

In various aspects, the compound is selected from:

or a pharmaceutically acceptable salt thereof.

In various aspects, n is 0, 1, or 2. In a still further aspect, n is 0or 1. In yet a further aspect, n is 1 or 2. In an even further aspect, nis 0 or 2. In a still further aspect, n is 0. In yet a further aspect, nis 1. In an even further aspect, n is 2.

a. R^(1A), R^(1B), R^(1C), R^(1D), and R^(E) Groups

In one aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹, or two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)groups are covalently bonded and, together with the intermediate atoms,comprise a 5- or 6-membered cycloalkyl, a 5- or 6-memberedheterocycloalkyl, a 6-membered aryl, or a 5- or 6-membered heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹. In a further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, —F, —Cl, —CN, —NH₂,—OH, —NO₂, methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, —CCl₃,—CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —CH₂CN, —CH₂CH₂CN,—CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F,—OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂Cl,—OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In astill further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂,methyl, ethyl, ethenyl, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F,—CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCCl₃,—OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃,—OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)CH₂CH₃, —CH₂NH₂,—CH₂CH₂NH₂, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In yet a further aspect,each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, —CCl₃,—CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CN, —CH₂OH, —OCCl₃, —OCF₃,—OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₃, —NHCH₃, —N(CH₃)₂, —CH₂NH₂,—C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In afurther aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂,methyl, ethyl, n-propyl, isopropyl, ethenyl, propenyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹. In a still further aspect, each of R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, ethyl, ethenyl,—C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In yet a further aspect, each ofR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, Cy¹, and —OCy¹.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl.In a further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, ethenyl, and propenyl. In a still further aspect, each ofR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, eachof R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen and methyl.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 haloalkyl, C1-C4 cyanoalkyl, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. Ina further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂,—CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F,—CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —CH₂CN,—CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and—OCy¹. In a still further aspect, each of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F,—CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN, —CH₂CH₂CN, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and—OCy¹. In yet a further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, —F, —Cl, —CN, —NH₂,—OH, —NO₂, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CN, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1c)is independently selected from hydrogen, C1-C4 haloalkyl, and C1-C4cyanoalkyl. In a further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, —CCl₃, —CF₃, —CHCl₂,—CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH(CH₃)CH₂CN. In a still further aspect, each of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is independently selected from hydrogen,—CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN,and —CH₂CH₂CN. In yet a further aspect, each of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is independently selected from hydrogen, —CCl₃, —CF₃,—CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, and —CH₂CN.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, —C(O)R¹⁰, —CO₂R¹¹,Cy¹, and —OCy¹. In a further aspect, each of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH,—OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F,—OCH₂CH₂CH₂Cl, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. Ina still further aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is independently selected from hydrogen, —F, —Cl, —CN, —NH₂, —OH,—NO₂, —CH₂OH, —CH₂CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹. In yet a further aspect, each of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, —CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₃, —C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected fromhydrogen, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCCl₃, —OCF₃,—OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, each of R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected fromhydrogen, —CH₂OH, —CH₂CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, and —OCH₂CH₃. In yet a furtheraspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂,—OCHF₂, —OCH₂Cl, —OCH₂F, and —OCH₃.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl,—C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In a further aspect, each of R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃, —N(CH₂CH₃)CH₂CH₂CH₃,—N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—C(O)R¹⁰, —CO₂R¹¹, Cy¹, and —OCy¹. In a still further aspect, each ofR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₃)CH₂CH₃, —CH₂NH₂, —CH₂CH₂NH₂, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹. In yet a further aspect, each of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, —NHCH₃, —N(CH₃)₂, —CH₂NH₂, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyselected from hydrogen, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂,—N(CH₃)₂, —N(CH₃)CH₂CH₃, —N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂,—CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still furtheraspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₃)CH₂CH₃, —CH₂NH₂, and —CH₂CH₂NH₂. In yet a further aspect, each ofR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen, —NHCH₃, —N(CH₃)₂, and —CH₂NH₂.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4haloalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, eachof R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independently selectedfrom hydrogen, —F, —Cl, methyl, ethyl, n-propyl, isopropyl, —CCl₃, —CF₃,—CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —OCCl₃, —OCF₃, —OCHCl₂,—OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, each of R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) is independently selected fromhydrogen, —F, —Cl, methyl, ethyl, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl,—CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, and —OCH₂CH₃. In yet a furtheraspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —F, —Cl, methyl, —CCl₃, —CF₃,—CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, and —OCH₃.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is independently selected from hydrogen and halogen. In a furtheraspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —F, —Cl, and —Br. In a stillfurther aspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, —F, and —Cl. In yet a furtheraspect, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen and —F. In an even further aspect,each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) is independentlyselected from hydrogen and —Cl.

In various aspects, each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e)is hydrogen. In a further aspect, at least one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is hydrogen. In a still further aspect, atleast two of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are hydrogen. Inyet a further aspect, at least three of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) are hydrogen. In an even further aspect, at least four ofR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are hydrogen.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered cycloalkyl, a 5- or 6-memberedheterocycloalkyl, a 6-membered aryl, or a 5- or 6-membered heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a further aspect, two adjoining R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) groups are covalently bonded and, together with theintermediate atoms, comprise a 5- or 6-membered cycloalkyl, a 5- or6-membered heterocycloalkyl, a 6-membered aryl, or a 5- or 6-memberedheteroaryl, and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a still further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkyl, a5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a 5- or6-membered heteroaryl, and is substituted with 0 or 1 group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkyl, a5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a 5- or6-membered heteroaryl, and is monosubstituted with a group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkyl, a5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a 5- or6-membered heteroaryl, and is unsubstituted.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered cycloalkyl or a 5- or 6-memberedheterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a further aspect, two adjoiningR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bondedand, together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl or a 5- or 6-membered heterocycloalkyl, and is substitutedwith 0, 1, or 2 groups independently selected from halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In astill further aspect, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered cycloalkyl or a 5- or 6-memberedheterocycloalkyl, and is substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkyl or a5- or 6-membered heterocycloalkyl, and is monosubstituted with a groupselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkyl or a5- or 6-membered heterocycloalkyl, and is unsubstituted.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered cycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, twoadjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered cycloalkyl substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered cycloalkylmonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even furtheraspect, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groupsare covalently bonded and, together with the intermediate atoms,comprise an unsubstituted 5- or 6-membered cycloalkyl.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered heterocycloalkyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered heterocycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, twoadjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered heterocycloalkyl substituted with 0 or 1 group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In aneven further aspect, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise an unsubstituted 5- or 6-membered heterocycloalkyl.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 6-membered aryl or a 5- or 6-membered heteroaryl, andis substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a further aspect, two adjoining R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) groups are covalently bonded and, together with theintermediate atoms, comprise a 6-membered aryl or a 5- or 6-memberedheteroaryl, and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a still further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered aryl or a 5- or6-membered heteroaryl, and is substituted with 0 or 1 group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered aryl or a 5- or6-membered heteroaryl, and is monosubstituted with a group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered aryl or a 5- or6-membered heteroaryl, and is unsubstituted.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 6-membered aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a further aspect, two adjoiningR^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bondedand, together with the intermediate atoms, comprise a 6-membered arylsubstituted with 0, 1, or 2 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In astill further aspect, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 6-membered aryl substituted with 0 or 1 group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered aryl monosubstitutedwith a group selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, twoadjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise anunsubstituted 6-membered aryl.

In various aspects, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered heteroaryl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered heteroaryl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, twoadjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groups arecovalently bonded and, together with the intermediate atoms, comprise a5- or 6-membered heteroaryl substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, two adjoining R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) groups are covalently bonded and, togetherwith the intermediate atoms, comprise a 5- or 6-membered heteroarylmonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even furtheraspect, two adjoining R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) groupsare covalently bonded and, together with the intermediate atoms,comprise an unsubstituted 5- or 6-membered heteroaryl.

b. R² Groups

In one aspect, R² is selected from hydrogen and C1-C4 alkyl. In afurther aspect, R² is selected from hydrogen, methyl, ethyl, n-propyl,and isopropyl. In a still further aspect, R² is selected from hydrogen,methyl, and ethyl. In yet a further aspect, R² is selected from hydrogenand ethyl. In an even further aspect, R² is selected from hydrogen andmethyl.

In various aspects, R² is C1-C4 alkyl. In a further aspect, R² isselected from methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, R² is selected from methyl and ethyl. In yet a further aspect,R² is ethyl. In an even further aspect, R² is methyl.

In various aspects, R² is hydrogen.

c. R^(3A), R^(3B), R^(3C), and R^(3D) Groups

In one aspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,each of R^(3a), R^(3b), R^(3c), and R^(3d) is independently selectedfrom hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, ethyl, n-propyl,isopropyl, ethenyl, propenyl, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F,—CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl,—CH(CH₃)CH₂F, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂,—OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl, —OCH₂CH₂CH₂F,—OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, ethyl, ethenyl, —CCl₃,—CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN,—CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —N(CH₃)CH₂CH₃, —CH₂NH₂, and —CH₂CH₂NH₂. In yet a furtheraspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) is independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, methyl, —CCl₃,—CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CN, —CH₂OH, —OCCl₃, —OCF₃,—OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₃, —NHCH₃, —N(CH₃)₂, and —CH₂NH₂.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen, —F,—Cl, —CN, —NH₂, —OH, —NO₂, methyl, ethyl, n-propyl, isopropyl, ethenyl,and propenyl. In a still further aspect, each of R^(3a), R^(3b), R^(3c),and R^(3d) is independently selected from hydrogen, —F, —Cl, —CN, —NH₂,—OH, —NO₂, methyl, ethyl, and ethenyl. In yet a further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, and methyl.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, C1-C4 alkyl, and C2-C4 alkenyl. Ina further aspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, methyl, ethyl, n-propyl,isopropyl, ethenyl, and propenyl. In a still further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, methyl, ethyl, and ethenyl. In yet a further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen and methyl.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —CCl₃, —CF₃, —CHCl₂, —CHF₂,—CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH(CH₃)CH₂CN. In a still further aspect, each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, —F, —Cl,—CN, —NH₂, —OH, —NO₂, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F,—CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN, and —CH₂CH₂CN. In yet a further aspect,each of R^(3a), R^(3b), R^(3c), and R^(3d) is independently selectedfrom hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —CCl₃, —CF₃, —CHCl₂,—CHF₂, —CH₂Cl, —CH₂F, and —CH₂CN.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, C1-C4 haloalkyl, and C1-C4cyanoalkyl. In a further aspect, each of R^(3a), R^(3b), R^(3c), andR^(3d) is independently selected from hydrogen, —CCl₃, —CF₃, —CHCl₂,—CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F,—CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH(CH₃)CH₂CN. In a still further aspect, each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, —CCl₃, —CF₃,—CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CN, and—CH₂CH₂CN. In yet a further aspect, each of R^(3a), R^(3b), R^(3c), andR^(3d) is independently selected from hydrogen, —CCl₃, —CF₃, —CHCl₂,—CHF₂, —CH₂Cl, —CH₂F, and —CH₂CN.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a furtheraspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) is independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂,—OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl, —OCH₂CH₂CH₂F,—OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and—OCH(CH₃)₂. In a still further aspect, each of R^(3a), R^(3b), R^(3c),and R^(3d) is independently selected from hydrogen, —F, —Cl, —CN, —NH₂,—OH, —NO₂, —CH₂OH, —CH₂CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl,—OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, and —OCH₂CH₃. In yet a furtheraspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) is independentlyselected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —CH₂OH, —OCCl₃,—OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F, and —OCH₃.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, and C1-C4 alkoxy. In a further aspect, each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂,—OCHF₂, —OCH₂Cl, —OCH₂F, —OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₂CH₂CH₂Cl,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂Cl, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, and —OCH(CH₃)₂. In a still further aspect, each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,—CH₂OH, —CH₂CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F,—OCH₂CH₂Cl, —OCH₂CH₂F, —OCH₃, and —OCH₂CH₃. In yet a further aspect,each of R^(3a), R^(3b), R^(3c), and R^(3d) is independently selectedfrom hydrogen, —CH₂OH, —OCCl₃, —OCF₃, —OCHCl₂, —OCHF₂, —OCH₂Cl, —OCH₂F,and —OCH₃.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Ina further aspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₃)CH₂CH₃, —CH₂NH₂, and —CH₂CH₂NH₂. In yet a further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, —Cl, —CN, —NH₂, —OH, —NO₂, —NHCH₃, —N(CH₃)₂, and —CH₂NH₂.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a further aspect, each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)CH₂CH₃, —CH₂NH₂, and—CH₂CH₂NH₂. In yet a further aspect, each of R^(3a), R^(3b), R^(3c), andR^(3d) is independently selected from hydrogen, —NHCH₃, —N(CH₃)₂, and—CH₂NH₂.

In various aspects, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen and halogen. In a further aspect,each of R^(3a), R^(3b), R^(3c), and R^(3d) is independently selectedfrom hydrogen, —F, —Cl, and —Br. In a still further aspect, each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen, —F, and —Cl. In yet a further aspect, each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen and —Cl. Inan even further aspect, each of R^(3a), R^(3b), R^(3c), and R^(3d) isindependently selected from hydrogen and —F.

In various aspects, each of R^(3a) and R^(3d) is hydrogen and each ofR^(3b) and R^(3c) is halogen. In a further aspect, each of R^(3a) andR^(3d) is hydrogen and each of R^(3b) and R^(3c) is independentlyselected from —F, —Cl, and —Br. In a still further aspect, each ofR^(3a) and R^(3d) is hydrogen and each of R^(3b) and R^(3c) isindependently selected from —F and —Cl. In yet a further aspect, each ofR^(3a) and R^(3d) is hydrogen and each of R^(3b) and R^(3c) is —F.

d. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl.In a further aspect, R⁴ is selected from hydrogen, —F, —Cl, —Br, methyl,ethyl, n-propyl, and isopropyl. In a still further aspect, R⁴ isselected from hydrogen, —F, —Cl, methyl, and ethyl. In yet a furtheraspect, R⁴ is selected from hydrogen, —F, and methyl.

In various aspects, R⁴ is selected from hydrogen and halogen. In afurther aspect, R⁴ is selected from hydrogen, —F, —Cl, and —Br. In astill further aspect, R⁴ is selected from hydrogen, —F, and —Cl. In yeta further aspect, R⁴ is selected from hydrogen and —Cl. In an evenfurther aspect, R⁴ is selected from hydrogen and —F.

In various aspects, R⁴ is selected from hydrogen and C1-C4 alkyl. In afurther aspect, R⁴ is selected from hydrogen, methyl, ethyl, n-propyl,and isopropyl. In a still further aspect, R⁴ is selected from hydrogen,methyl, and ethyl. In yet a further aspect, R⁴ is selected from hydrogenand ethyl. In an even further aspect, R⁴ is selected from hydrogen andmethyl.

In various aspects, R⁴ is halogen. In a further aspect, R⁴ is selectedfrom —F, —Cl, and —Br. In a still further aspect, R⁴ is selected from —Fand —Cl. In yet a further aspect, R⁴ is —Cl. In an even further aspect,R⁴ is —F.

In various aspects, R⁴ is C1-C4 alkyl. In a further aspect, R⁴ isselected from methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, R⁴ is selected from methyl and ethyl. In yet a further aspect,R⁴ is ethyl. In an even further aspect, R⁴ is methyl.

In various aspects, R⁴ is hydrogen.

e. R¹⁰ Groups

In one aspect, R¹⁰, when present, is selected from hydrogen, —NH₂, C1-C4alkyl, C1-C4 haloalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,and C1-C4 aminoalkyl. In a further aspect, R¹⁰, when present, isselected from hydrogen, —NH₂, methyl, ethyl, n-propyl, isopropyl, —CCl₃,—CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, —CH₂CH₂F, —CH₂CH₂CH₂Cl,—CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl, —CH(CH₃)CH₂F, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃, —N(CH₂CH₃)CH₂CH₂CH₃,—N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂.In a still further aspect, R¹⁰, when present, is selected from hydrogen,—NH₂, methyl, ethyl, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F,—CH₂CH₂Cl, —CH₂CH₂F, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—CH₂NH₂, and —CH₂CH₂NH₂. In yet a further aspect, R¹⁰, when present, isselected from hydrogen, —NH₂, methyl, —CCl₃, —CF₃, —CHCl₂, —CHF₂,—CH₂Cl, —CH₂F, —NHCH₃, —N(CH₃)₂, and —CH₂NH₂.

In various aspects, R¹⁰, when present, is selected from hydrogen andC1-C4 alkyl. In a further aspect, R¹⁰, when present, is selected fromhydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, R¹⁰, when present, is selected from hydrogen, methyl, and ethyl.In yet a further aspect, R¹⁰, when present, is selected from hydrogenand ethyl. In an even further aspect, R¹⁰, when present, is selectedfrom hydrogen and methyl.

In various aspects, R¹⁰, when present, is selected from hydrogen andC1-C4 haloalkyl. In a further aspect, R¹⁰, when present, is selectedfrom hydrogen, —CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl,—CH₂CH₂F, —CH₂CH₂CH₂Cl, —CH₂CH₂CH₂F, —CH(CH₃)CH₂Cl, and —CH(CH₃)CH₂F. Ina still further aspect, R¹⁰, when present, is selected from hydrogen,—CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, —CH₂F, —CH₂CH₂Cl, and —CH₂CH₂F. Inyet a further aspect, R¹⁰, when present, is selected from hydrogen,—CCl₃, —CF₃, —CHCl₂, —CHF₂, —CH₂Cl, and —CH₂F.

In various aspects, R¹⁰, when present, is selected from hydrogen, —NH₂,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Ina further aspect, R¹⁰, when present, is selected from hydrogen, —NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)CH₂CH₃,—N(CH₂CH₃)CH₂CH₂CH₃, —N(CH₃)CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, and —CH(CH₃)CH₂NH₂. In a still further aspect, R¹⁰, whenpresent, is selected from hydrogen, —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₃)CH₂CH₃, —CH₂NH₂, and —CH₂CH₂NH₂. In yet a further aspect, R¹⁰,when present, is selected from hydrogen, —NH₂, —NHCH₃, —N(CH₃)₂, and—CH₂NH₂.

f. R¹¹ Groups

In one aspect, R¹¹, when present, is selected from hydrogen and C1-C4alkyl. In a further aspect, R¹¹, when present, is selected fromhydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, R¹¹, when present, is selected from hydrogen, methyl, and ethyl.In yet a further aspect, R¹¹, when present, is selected from hydrogenand ethyl. In an even further aspect, R¹¹, when present, is selectedfrom hydrogen and methyl.

In various aspects, R¹¹, when present, is C1-C4 alkyl. In a furtheraspect, R¹¹, when present, is selected from methyl, ethyl, n-propyl, andisopropyl. In a still further aspect, R¹¹, when present, is selectedfrom methyl and ethyl. In yet a further aspect, R¹¹, when present, isethyl. In an even further aspect, R¹¹, when present, is methyl.

In various aspects, R¹¹, when present, is hydrogen.

g. Cy¹ Groups

In one aspect, Cy^(l) is selected from C6 aryl, C2-C5 heteroaryl, C3-C6cycloalkyl, and C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,Cy^(l) is selected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, andC2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy^(l) isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, Cy¹ is selected from C6 aryl, C2-C5heteroaryl, C3-C6 cycloalkyl, and C2-C5 heterocycloalkyl, and ismonosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even furtheraspect, Cy¹ is selected from C6 aryl, C2-C5 heteroaryl, C3-C6cycloalkyl, and C2-C5 heterocycloalkyl, and is unsubstituted.

In various aspects, Cy¹ is selected from C6 aryl and C2-C5 heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a further aspect, Cy¹ is selected from C6 aryl and C2-C5heteroaryl, and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a still further aspect, Cy¹ is selected from C6 aryl andC2-C5 heteroaryl, and is substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, Cy¹ is selected from C6 aryl andC2-C5 heteroaryl, and is monosubstituted with a group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, Cy¹ is selected from C6 aryl andC2-C5 heteroaryl, and is unsubstituted.

In various aspects, Cy^(l) is C6 aryl substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,Cy¹ is C6 aryl substituted with 0, 1, or 2 groups independently selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a still further aspect, Cy¹ is C6 aryl substituted with 0or 1 group selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy¹ is C6aryl monosubstituted with a group selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even furtheraspect, Cy¹ is unsubstituted C6 aryl substituted.

In various aspects, Cy¹ is C2-C5 heteroaryl substituted with 0, 1, 2, or3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C5heteroaryls include, but are not limited to, furan, pyrrole, thiophene,oxazole, isothiazole, pyridine, and triazine. In a further aspect, Cy¹is C2-C5 heteroaryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In a still further aspect, Cy¹ is C2-C5 heteroarylsubstituted with 0 or 1 group selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet a furtheraspect, Cy¹ is C2-C5 heteroaryl monosubstituted with a group selectedfrom halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, Cy¹ is unsubstituted C2-C5heteroaryl.

In various aspects, Cy¹ is selected from C3-C6 cycloalkyl and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy¹ is selectedfrom C3-C6 cycloalkyl and C2-C5 heterocycloalkyl, and is substitutedwith 0, 1, or 2 groups independently selected from halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In astill further aspect, Cy¹ is selected from C3-C6 cycloalkyl and C2-C5heterocycloalkyl, and is substituted with 0 or 1 group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In yet a further aspect, Cy¹ is selected from C3-C6cycloalkyl and C2-C5 heterocycloalkyl, and is monosubstituted with agroup selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino,and C1-C4 aminoalkyl. In an even further aspect, Cy¹ is selected fromC3-C6 cycloalkyl and C2-C5 heterocycloalkyl, and is unsubstituted.

In various aspects, Cy¹ is C3-C6 cycloalkyl substituted with 0, 1, 2, or3 groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect,Cy^(l) is C3-C6 cycloalkyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy¹ isC3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In yet afurther aspect, Cy¹ is C3-C6 cycloalkyl monosubstituted with a groupselected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, Cy¹ is unsubstituted C3-C6cycloalkyl.

In various aspects, Cy¹ is C2-C5 heterocycloalkyl substituted with 0, 1,2, or 3 groups independently selected from halogen, —CN, —NH₂, —OH,—NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C5heterocycloalkyls include, but are not limited to, thiirane, oxirane,aziridine, thietane, azetidine, oxetane, pyrrolidine, imidazolidine,tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane,and morpholine. In a further aspect, Cy¹ is C2-C5 heterocycloalkylsubstituted with 0, 1, or 2 groups independently selected from halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In astill further aspect, Cy¹ is C2-C5 heterocycloalkyl substituted with 0or 1 group selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl. In yet a further aspect, Cy¹ isC2-C5 heterocycloalkyl monosubstituted with a group selected fromhalogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl. In an even further aspect, Cy^(l) is unsubstituted C2-C5heterocycloalkyl.

2. Example Biaryl Aminomaleimides

In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

In one aspect, a compound can be present as:

or a pharmaceutically acceptable salt thereof.

3. Prophetic Biaryl Aminomaleimide Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. It is anticipatedthat the prophetic compounds would be active as modulators of hemeoxygenase-1 signaling, and such activity can be determined using theassay methods described herein below.

In one aspect, a compound can be selected from:

In one aspect, a compound can be selected from:

It is contemplated that one or more compounds can optionally be omittedfrom the disclosed invention.

It is understood that the disclosed compounds can be used in connectionwith the disclosed methods, compositions, kits, and uses.

It is understood that pharmaceutical acceptable derivatives of thedisclosed compounds can be used also in connection with the disclosedmethods, compositions, kits, and uses. The pharmaceutical acceptablederivatives of the compounds can include any suitable derivative, suchas pharmaceutically acceptable salts as discussed below, isomers,radiolabeled analogs, tautomers, and the like.

C. PHARMACEUTICAL COMPOSITIONS

In one aspect, disclosed are pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier.

Thus, in one aspect, disclosed are pharmaceutical compositionscomprising a therapeutically effective amount of a compound having astructure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structurerepresented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structureselected from

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In one aspect, disclosed are pharmaceutical compositions comprising atherapeutically effective amount of a compound having a structure:

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In various aspects, the compounds and compositions of the invention canbe administered in pharmaceutical compositions, which are formulatedaccording to the intended method of administration. The compounds andcompositions described herein can be formulated in a conventional mannerusing one or more physiologically acceptable carriers or excipients. Forexample, a pharmaceutical composition can be formulated for local orsystemic administration, intravenous, topical, or oral administration.

The nature of the pharmaceutical compositions for administration isdependent on the mode of administration and can readily be determined byone of ordinary skill in the art. In various aspects, the pharmaceuticalcomposition is sterile or sterilizable. The therapeutic compositionsfeatured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used includebuffers (for example, citrate buffer, phosphate buffer, acetate buffer,and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, polypeptides (for example, serum albumin), EDTA, sodiumchloride, liposomes, mannitol, sorbitol, water, and glycerol. Thenucleic acids, polypeptides, small molecules, and other modulatorycompounds featured in the invention can be administered by any standardroute of administration. For example, administration can be parenteral,intravenous, subcutaneous, or oral. A modulatory compound can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made foradministration by drops into the ear, for injection, or for ingestion;gels or powders can be made for ingestion or topical application.Methods for making such formulations are well known and can be found in,for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro,ed., Mack Publishing Co., Easton, Pa. 1990.

In various aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In various aspects, the pharmaceutical compositions of this inventioncan include a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of the compounds of the invention. Thecompounds of the invention, or pharmaceutically acceptable saltsthereof, can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques.

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an evenfurther aspect, the human is a patient.

In a further aspect, the pharmaceutical composition is used to treat adisorder associated with heme oxygenase-1 (HO-1) signaling such as, forexample, kidney diseases including, but not limited to, chronic kidneydisease and acute kidney injury.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

D. METHODS OF MAKING BIARYL AMINOMALEIMIDES

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Route I, as described andexemplified below. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

1. Route I

In one aspect, substituted biaryl aminomaleimides can be prepared asshown below.

Compounds are represented in generic form, where X is a halogen, andwith other substituents as noted in compound descriptions elsewhereherein. A more specific example is set forth below.

In one aspect, compounds of type 1.6, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.6 can be prepared by a coupling reaction between an appropriatemaleimide, e.g., 1.4 as shown above and an appropriate anilinederivative, e.g., 1.5 as shown above. Appropriate maleimides andappropriate aniline derivatives are commercially available or preparedby methods known to one skilled in the art. The coupling reaction iscarried out in the presence of an appropriate solvent, e.g., ethanol, atan appropriate temperature, e.g., 80° C. As can be appreciated by oneskilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 1.1 and1.2), can be substituted in the reaction to provide substituted biarylaminomaleimide derivatives similar to Formula 1.3.

E. TREATING A DISORDER ASSOCIATED WITH HO-1 SIGNALING

In one aspect, disclosed are methods for treating a disorder associatedwith heme oxygenase-1 signaling in a subject, the method comprisingadministering to the subject an effective amount of a disclosedcompound, thereby treating the disorder.

Thus, in one aspect, disclosed are methods for treating a disorderassociated with HO-1 signaling dysfunction in a subject in need thereof,the method comprising administering to the subject an effective amountof a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby treating the disorderin the subject.

In one aspect, disclosed are methods for treating a disorder associatedwith HO-1 signaling dysfunction in a subject in need thereof, the methodcomprising administering to the subject an effective amount of acompound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, thereby treating the disorder in the subject.

In one aspect, disclosed are methods for treating a disorder associatedwith HO-1 signaling dysfunction in a subject in need thereof, the methodcomprising administering to the subject an effective amount of acompound having a structure selected from:

or a pharmaceutically acceptable salt thereof, thereby treating thedisorder in the subject.

In one aspect, disclosed are methods for treating a disorder associatedwith HO-1 signaling dysfunction in a subject in need thereof, the methodcomprising administering to the subject an effective amount of acompound having a structure:

or a pharmaceutically acceptable salt thereof, thereby treating thedisorder in the subject.

In a further aspect, the subject has been diagnosed with a need fortreatment of the disorder prior to the administering step. In a stillfurther aspect, the subject is at risk for developing the disorder priorto the administering step.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is a human.

In a further aspect, the method further comprises the step ofidentifying a subject in need of treatment of the disorder.

In a further aspect, the disorder associated with HO-1 signalingdysfunction is a kidney disease. In a still further aspect, the kidneydisease is chronic kidney disease or acute kidney injury (AKI).

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the method further comprises the step ofadministering a therapeutically effective amount of at least one agentassociated with the treatment of a disorder associated with HO-1signaling dysfunction. In a still further aspect, the agent is anangiotensin-converting enzyme (ACE) inhibitor or an angiotensin IIreceptor blocker.

In a further aspect, the compound and the agent are administeredsequentially. In a still further aspect, the compound and the agent areadministered simultaneously.

In a further aspect, the compound and the agent are co-formulated. In astill further aspect, the compound and the agent are co-packaged.

In a further aspect, the compound is administered as a single activeagent.

F. MODIFYING HO-1 SIGNALING IN A SUBJECT

In one aspect, disclosed are methods for modifying HO-1 signaling in asubject, the method comprising administering to the subject an effectiveamount of a disclosed compound, thereby modifying HO-1 signaling in thesubject. Also disclosed are methods for increasing HO-1 signaling in asubject, the method comprising administering a compound that increasesHO-1 signaling, wherein the ability of the compound to increase HO-1signaling is determined by a disclosed method.

Thus, in one aspect, disclosed are methods for modifying HO-1 signalingin a subject, the method comprising administering to the subject aneffective amount of a compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

In one aspect, disclosed are methods for modifying HO-1 signaling in asubject, the method comprising administering to the subject an effectiveamount of a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3e), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3e), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, thereby modifying HO-1 signaling in the subject.

In one aspect, disclosed are methods for modifying HO-1 signaling in asubject, the method comprising administering to the subject an effectiveamount of a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

In one aspect, disclosed are methods for modifying HO-1 signaling in asubject, the method comprising administering to the subject an effectiveamount of a compound having a structure:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

In one aspect, disclosed are methods of increasing heme oxygenase-1(HO-1) signaling in a subject, the method comprising administering acompound that increases HO-1 signaling, wherein the ability of thecompound to increase HO-1 signaling is determined by: (a) contacting acell with a candidate compound, wherein the cell comprises: (i) a vectorcomprising: (1) a promoter operably linked to a nucleic acid comprisingthe sequence of NCBI accession no. Z82244; (2) an enhancer, wherein theenhancer comprises the sequence of SEQ ID NO: 1; and (3) a selectablemarker; or (ii) a vector comprising: (1) a promoter operably linked to anucleic acid comprising a triple mutant of the sequence of NCBIaccession no. Z82244; and (2) a selectable marker; wherein the vectorexpresses HO-1 or a mutant thereof, (b) determining expression of theselectable marker in the cell; and (c) identifying the candidatecompound as a compound that that increases HO-1 signaling whenexpression of the selectable marker is increased in the cell.

In a further aspect, modifying is increasing. In a still further aspect,modifying is activating.

In a further aspect, the subject has been diagnosed with a disorderassociated with HO-1 signaling prior to the administering step. In stilla further aspect, the subject has been diagnosed with a need formodifying HO-1 signaling prior to the administering step. In yet afurther aspect, the subject has been diagnosed with a need for treatmentof a disorder associated with HO-I signaling dysfunction prior to theadministering step.

In a further aspect, the method further comprises the step ofidentifying a subject in need of treatment of a disorder associated withHO-I signaling dysfunction.

In a further aspect, the disorder associated with HO-1 signalingdysfunction is a kidney disease. In a still further aspect, the kidneydisease is chronic kidney disease or acute kidney injury (AKI).

In a further aspect, the effective amount is a therapeutically effectiveamount. In a still further aspect, the effective amount is aprophylactically effective amount.

In a further aspect, the method further comprises the step ofadministering a therapeutically effective amount of at least one agentassociated with the treatment of a disorder associated with HO-1signaling dysfunction. In a still further aspect, the agent is a anangiotensin-converting enzyme (ACE) inhibitor or an angiotensin IIreceptor blocker.

In a further aspect, the compound and the agent are administeredsequentially. In a still further aspect, the compound and the agent areadministered simultaneously.

In a further aspect, the compound and the agent are co-formulated. In astill further aspect, the compound and the agent are co-packaged.

In a further aspect, the compound is administered as a single activeagent.

G. MODIFYING HO-I SIGNALING IN AT LEAST ONE CELL

In one aspect, disclosed are methods for modifying HO-1 signaling in acell, the method comprising contacting the cell with an effective amountof a disclosed compound, thereby modifying HO-1 signaling in the cell.

Thus, in one aspect, disclosed are methods for modifying HO-1 signalingin a cell, the method comprising contacting the cell with an effectiveamount of a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the cell.

In one aspect, disclosed are methods for modifying HO-1 signaling in acell, the method comprising contacting the cell with an effective amountof a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, thereby modifying HO-1 signaling in the cell.

In one aspect, disclosed are methods for modifying HO-1 signaling in acell, the method comprising contacting the cell with an effective amountof a compound having a structure selected from:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the cell.

In one aspect, disclosed are methods for modifying HO-1 signaling in acell, the method comprising contacting the cell with an effective amountof a compound having a structure:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the cell.

In a further aspect, modifying is increasing. In a still further aspect,modifying is activating.

In a further aspect, the cell is mammalian. In a still further aspect,the cell is human.

In a further aspect, the cell has been isolated from a human prior tothe administering step.

In a further aspect, contacting is via administration to a subject. In astill further aspect, the subject has been diagnosed with a need formodification of HO-I signaling prior to the administering step. In yet afurther aspect, the subject has been diagnosed with a need for treatmentof a disorder associated with HO-I signaling dysfunction.

In a further aspect, the disorder associated with HO-1 signalingdysfunction is a kidney disease. In a still further aspect, the kidneydisease is chronic kidney disease or acute kidney injury (AKI).

H. IDENTIFYING A COMPOUND THAT MODULATES HO-1 SIGNALING

In one aspect, disclosed are methods of identifying a compound thatmodulates heme oxygenase-1 (HO-1) signaling, the method comprising: (a)contacting a cell with a candidate compound, wherein the cell comprises:(i) a vector comprising: (1) a promoter operably linked to a nucleicacid comprising the sequence of NCBI Accession No. Z82244; (2) anenhancer, wherein the enhancer comprises the sequence of SEQ ID NO: 1;and (3) a selectable marker; or (ii) a vector comprising: (1) a promoteroperably linked to a nucleic acid comprising a triple mutant of thesequence of NCBI Accession No. Z82244; and (2) a selectable marker;wherein the vector expresses HO-1 or a mutant thereof, (b) determiningexpression of the selectable marker in the cell; and (c) identifying thecandidate compound as a compound that modulates HO-1 signaling whenexpression of the selectable marker is modulated in the cell. Alsodisclosed are compounds that modulate heme oxygenase-1 (HO-1) identifiedby a disclosed method.

In various aspects, the cell is a eukaryotic cell. In a further aspect,the eukaryotic cell is a mammalian or human cell.

In various aspects, the method further comprises purifying the compound.In a further aspect, the method further comprises isolating thecompound.

In various aspects, the selectable marker is a fluorescent marker.

In various aspects, the candidate compound increases expression of theselectable marker in the cell. In a further aspect, the candidatecompound decreases expression of the selectable marker in the cell.

In various aspects, the compound that modulates HO-1 identified by adisclosed method has a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

In various aspects, the compound that modulates HO-1 identified by adisclosed method has a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, thereby modifying HO-1 signaling in the subject.

In various aspects, the compound that modulates HO-1 identified by adisclosed method has a structure selected from:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

In various aspects, the compound that modulates HO-1 identified by adisclosed method has a structure:

or a pharmaceutically acceptable salt thereof, thereby modifying HO-1signaling in the subject.

I. ADDITIONAL METHODS OF USING THE COMPOUNDS

The compounds and pharmaceutical compositions of the invention areuseful in treating or controlling disorders associated with HO-1signaling dysfunction, and, in particular, a kidney disease.

Examples of disorders associated with HO-1 signaling dysfunction forwhich the compounds and compositions can be useful in treating, include,but are not limited to, kidney diseases such as, for example, chronickidney disease and acute kidney injury.

To treat or control the disorder, the compounds and pharmaceuticalcompositions comprising the compounds are administered to a subject inneed thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, areptile, or an amphibian. The subject can be a human, non-human primate,horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.The term does not denote a particular age or sex. Thus, adult andnewborn subjects, as well as fetuses, whether male or female, areintended to be covered. The subject is preferably a mammal, such as ahuman. Prior to administering the compounds or compositions, the subjectcan be diagnosed with a need for treatment of a disorder associated withHO-1 signaling dysfunction such as a kidney disease.

The compounds or compositions can be administered to the subjectaccording to any method. Such methods are well known to those skilled inthe art and include, but are not limited to, oral administration,transdermal administration, administration by inhalation, nasaladministration, topical administration, intravaginal administration,ophthalmic administration, intraaural administration, intracerebraladministration, rectal administration, sublingual administration, buccaladministration and parenteral administration, including injectable suchas intravenous administration, intra-arterial administration,intramuscular administration, and subcutaneous administration.Administration can be continuous or intermittent. A preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. A preparation can also be administeredprophylactically; that is, administered for prevention of a disorderassociated with HO-1 signaling dysfunction such as a kidney disease.

The therapeutically effective amount or dosage of the compound can varywithin wide limits. Such a dosage is adjusted to the individualrequirements in each particular case including the specific compound(s)being administered, the route of administration, the condition beingtreated, as well as the patient being treated. In general, in the caseof oral or parenteral administration to adult humans weighingapproximately 70 Kg or more, a daily dosage of about 10 mg to about10,000 mg, preferably from about 200 mg to about 1,000 mg, should beappropriate, although the upper limit may be exceeded. The daily dosagecan be administered as a single dose or in divided doses, or forparenteral administration, as a continuous infusion. Single dosecompositions can contain such amounts or submultiples thereof of thecompound or composition to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days.

1. Use of Compounds

In one aspect, the invention relates to the use of a disclosed compoundor a product of a disclosed method. In a further aspect, a use relatesto the manufacture of a medicament for the treatment of a disorderassociated with HO-1 signaling dysfunction in a subject.

Also provided are the uses of the disclosed compounds and products. Inone aspect, the invention relates to use of at least one disclosedcompound; or a pharmaceutically acceptable salt, hydrate, solvate, orpolymorph thereof. In a further aspect, the compound used is a productof a disclosed method of making.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof, foruse as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method of making, ora pharmaceutically acceptable salt, solvate, or polymorph thereof,wherein a pharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of the compound or the product of adisclosed method of making.

In various aspects, the use relates to a treatment of a disorderassociated with HO-1 signaling dysfunction in a subject. In one aspect,the use is characterized in that the subject is a human. In one aspect,the use is characterized in that the disorder associated with HO-1signaling dysfunction is a kidney disease.

In a further aspect, the use relates to the manufacture of a medicamentfor the treatment of a disorder associated with HO-1 signalingdysfunction in a subject.

It is understood that the disclosed uses can be employed in connectionwith the disclosed compounds, products of disclosed methods of making,methods, compositions, and kits. In a further aspect, the inventionrelates to the use of a disclosed compound or a disclosed product in themanufacture of a medicament for the treatment of a disorder associatedwith HO-1 signaling dysfunction in a mammal. In a further aspect, thedisorder associated with HO-1 signaling dysfunction is a kidney disease.

2. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treating a disorder associated with HO-1 signalingdysfunction in a subject having the disorder, the method comprisingcombining a therapeutically effective amount of a disclosed compound orproduct of a disclosed method with a pharmaceutically acceptable carrieror diluent.

As regards these applications, the present method includes theadministration to an animal, particularly a mammal, and moreparticularly a human, of a therapeutically effective amount of thecompound effective in the treatment of a disorder associated with HO-1signaling dysfunction (e.g., a kidney disease). The dose administered toan animal, particularly a human, in the context of the present inventionshould be sufficient to affect a therapeutic response in the animal overa reasonable timeframe. One skilled in the art will recognize thatdosage will depend upon a variety of factors including the condition ofthe animal and the body weight of the animal.

The total amount of the compound of the present disclosure administeredin a typical treatment is preferably between about 0.05 mg/kg and about100 mg/kg of body weight for mice, and more preferably between 0.05mg/kg and about 50 mg/kg of body weight for mice, and between about 100mg/kg and about 500 mg/kg of body weight for humans, and more preferablybetween 200 mg/kg and about 400 mg/kg of body weight for humans perdaily dose. This total amount is typically, but not necessarily,administered as a series of smaller doses over a period of about onetime per day to about three times per day for about 24 months, andpreferably over a period of twice per day for about 12 months.

The size of the dose also will be determined by the route, timing andfrequency of administration as well as the existence, nature and extentof any adverse side effects that might accompany the administration ofthe compound and the desired physiological effect. It will beappreciated by one of skill in the art that various conditions ordisease states, in particular chronic conditions or disease states, mayrequire prolonged treatment involving multiple administrations.

Thus, in one aspect, the invention relates to the manufacture of amedicament comprising combining a disclosed compound or a product of adisclosed method of making, or a pharmaceutically acceptable salt,solvate, or polymorph thereof, with a pharmaceutically acceptablecarrier or diluent.

3. Kits

In one aspect, disclosed are kits comprising a disclosed compound, andone or more of: (a) an agent associated with the treatment of a disorderassociated with HO-1 signaling dysfunction; (b) instructions foradministering the compound in connection with treating a disorderassociated with HO-1 signaling dysfunction; and (c) instructions fortreating a disorder associated with HO-1 signaling dysfunction.

Thus, in one aspect, disclosed are kits comprising a compound having astructure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein Ru, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, and one or more of: (a) anagent associated with the treatment of a disorder associated with HO-1signaling dysfunction; (b) instructions for administering the compoundin connection with treating a disorder associated with HO-1 signalingdysfunction; and (c) instructions for treating a disorder associatedwith HO-1 signaling dysfunction.

In one aspect, disclosed are kits comprising a compound having astructure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3e), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof, and one or more of: (a) an agent associated with the treatmentof a disorder associated with HO-1 signaling dysfunction; (b)instructions for administering the compound in connection with treatinga disorder associated with HO-1 signaling dysfunction; and (c)instructions for treating a disorder associated with HO-1 signalingdysfunction.

In one aspect, disclosed are kits comprising a compound having astructure selected from:

or a pharmaceutically acceptable salt thereof, and one or more of: (a)an agent associated with the treatment of a disorder associated withHO-1 signaling dysfunction; (b) instructions for administering thecompound in connection with treating a disorder associated with HO-1signaling dysfunction; and (c) instructions for treating a disorderassociated with HO-1 signaling dysfunction.

In one aspect, disclosed are kits comprising a compound having astructure:

or a pharmaceutically acceptable salt thereof, and one or more of: (a)an agent associated with the treatment of a disorder associated withHO-1 signaling dysfunction; (b) instructions for administering thecompound in connection with treating a disorder associated with HO-1signaling dysfunction; and (c) instructions for treating a disorderassociated with HO-1 signaling dysfunction.

In a further aspect, the disorder associated with HO-1 signalingdysfunction is a kidney disease. In a still further aspect, the kidneydisease chronic kidney disease or acute kidney injury (AKI).

In a further aspect, the agent is an angiotensin-converting enzyme (ACE)inhibitor or an angiotensin II receptor blocker.

In a further aspect, the compound and the agent are co-formulated. In afurther aspect, the compound and the agent are co-packaged.

The kits can also comprise compounds and/or products co-packaged,co-formulated, and/or co-delivered with other components. For example, adrug manufacturer, a drug reseller, a physician, a compounding shop, ora pharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

It is understood that the disclosed kits can be prepared from thedisclosed compounds, products, and pharmaceutical compositions. It isalso understood that the disclosed kits can be employed in connectionwith the disclosed methods of using.

The foregoing description illustrates and describes the disclosure.Additionally, the disclosure shows and describes only the preferredembodiments but, as mentioned above, it is to be understood that it iscapable to use in various other combinations, modifications, andenvironments and is capable of changes or modifications within the scopeof the invention concepts as expressed herein, commensurate with theabove teachings and/or the skill or knowledge of the relevant art. Theembodiments described herein above are further intended to explain bestmodes known by applicant and to enable others skilled in the art toutilize the disclosure in such, or other, embodiments and with thevarious modifications required by the particular applications or usesthereof. Accordingly, the description is not intended to limit theinvention to the form disclosed herein. Also, it is intended to theappended claims be construed to include alternative embodiments.

All publications and patent applications cited in this specification areherein incorporated by reference, and for any and all purposes, as ifeach individual publication or patent application were specifically andindividually indicated to be incorporated by reference. In the event ofan inconsistency between the present disclosure and any publications orpatent application incorporated herein by reference, the presentdisclosure controls.

J. EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Generation of pHOGL3/4.5+220

The generation of the pHOGL3/4.5+220 construct is described in Deshane,et al. (2010) “SpI regulates chromatin looping between an intronicenhancer and distal promoter of the human heme oxygenase-1 gene in renalcells” J Biol Chem 285(22): 16476-86. See also FIG. 1.

Briefly, BamHI sites were added to the 4.5-kb PCR product generated bylong-range PCR from a bacterial artificial chromosome clone containingportions of chromosome 22 (accession no. Z82244), including the HO-1gene. This fragment was cloned into the BglII restriction site of themultiple cloning region to make the parental clone (pHOGL3/4.5). The220-bp intronic enhancer was amplified with SalI sites on either end andcloned into the SalI site of the vector to generate pHOGL3/4.5+220.

2. Generation of pHOGL3/4.5+220 and pHOGL3/Triple Mutant

The Triple Mutant used for the counter-screen is described in Liby, etal. (2005) “The synthetic triterpenoids, CDDO and CDDO-imidazolide, arepotent inducers of heme oxygenase-1 and Nrf2/ARE signaling” Cancer Res65(11): 4789. See also FIG. 2.

Briefly, pHOGL3/4.5 was used as the parental clone. Mutations anddeletions were made sequentially using the QuikChange XL site-directedmutagenesis kit to create the pHOGL3/Triple Mutant.

3. DNA Sequences

The DNA sequence for the 220-bp enhancer is as follows:

(SEQ ID NO: 1) acaaggctgcatcttaaagcgattgagaacgtggcctgaatgaggatgggagtctcttgaaggcctgcccacaggtgggaggctcagcagttgggaaggaccccacccccagccagctttgtgttcacctttcccatttcctcctcagcatgccccaggatttgtcagaggccctgaaggaggccaccaaggaggtgcac acccaggcagagaa.

The DNA sequence for the 4.5-kb promoter is as follows:

(SEQ ID NO: 2)gcccagggtccttcctgccttccttggcaggtgggtccctgacctcctgcattgtggtcactcccaaccaaacacctcccgggaggcggaagttgcaatgagccaagatcaggccattgcactccagtgtgggcaacaaggtttttgcaagtggatgaaggctttccctgagtattcctcttgcttcctcccacctcctcctgtaactgaaggattgtcctgtcctccttaagcattcattctgcatgttaccccagcaggaccaggaaccccaaatacaaattttcctctattcctctaatcacttccatgcccttctcaagatgcatcaagaccctcaaggtcaggccgggcacggtggctcaagcctggaatcccagcactttgggaggctgaggagggcggatcacgaggtcaggagatcaagaccatcctggctaacacagtgaaacctggtctctactaaaaacacaaaaaattagccgggcgtggtcgcgggcacctgtagtcccagctactcgggaggctgaggcaggagaatggtgtgaacccgggaggcggagcttgcagtcacccaagatcgcgccaccgcactccagcctgggcaacagagcgaaaccccgtcacaaaaaaaaaaaagaaaaaagaaaaaaagaaaaaaaaagaccctcaaggtcatattcaaagggaaggaagtccagcccccttgaggcagctggctgaaaaacaggtttctcatatactaaaagaacttgggaaatgggaatcagaaatggataatcattttgttgctagcatgctccaagctagggtcattataaggtgatggagacaaggacataggctggcccaaggccacaggcacaggagacaaaaatacccgcaggacagagatgaaggctgatcccaggctaacagatgaccattagaacacagatgaaggccaggttaaactggtttattctggaaccccaaggatgaagagggagcccccggttcacttcagtatctcctctgttctcagtgggtaattatgatgagatggggccaaggttaagggtacacagtaagactggttcattccgaaaccctaaggatgaatgaggaacgccctgttcaggaaaggataacaggaaaataagaggatgccttcttttctgttttttttttctgctttgttctctctttgcaggtgggtaatcacgtcaccgtatgtcaggacatgcccctgcattctcaaaaactgggaagtttgatcacccaaatcttggaacaaaaagccacttttccttttgaatactgtttggcctaaaaatgaactgggagaaaattacaaaagtcagcctttctttctccaaaagaatccagtgcctctatgcaggaaatcctcaaattagccttctcaggtcttttataatcaacagcagaatgaggaggacagggataaagagacagagaaatgcagggaacagagagaggctcaactattggctgttttataagccctccagccccacccaggttgccctcagaatcccctcctaggtaactgccatcagcgccagaagccaggccactggcagataaactgcccccatgggataaatggggaaaagccccacatagcttgttccctttgccacaagctcagccactggaaacgggactgccctgagggtcataggaacccccccaggacagaatcccaacccctgatggccatgagctgaaggggttctctgccctggctggcttccaaatcagacattgtcattaacaggacaaagccaagggtaactttggaggcggcaagtaaaattataaatttccctcttgagttcaagagctgcctactctgtgctaatctccttatctgagcaactctcttccaaatcctgttgggtaatgggggaaaatggcaccttctttctccaaaagaaaaaaatctttatattacttaagggaccaaggagtttgagaccagcctgggcaacatagtgagaccctgtctccatcagaaacacaaaaaaattagccaggtggacgtggtggcacaggcctgtggtcctagctacttgggaggctagggtgggaggatcgcttgagcccgggtgatggaggctgcagtgagccgagatcgtgccactgcactccagcctgagtgacagagtgagaccccatcgcaaaaaaaaaaaaaaataagtcaaggatgatgatgatatagactcagggaatatcattaagtgaacgagaaattatctttattccccacttttaacatggggaaactgaggccccaggaagacaaccaagtattggctgaattgagctgagggagatctcaaatcactcaatagcgaccaccaccttcccaggcagctatcgaagttcccataatgggcagatggatcacctggggtcaggagttcgagaccagcctggccaacatgataaaaccccatctctactaaaaaaatacaaaaattagccggatgtggtataattacagctgtaatcccagctactagggaggatgaggcaggaaaattgcttgaacctgggagacaggttgcagtgagccgaaatcacggtggctcacacctgtaatcacagcactttgggaggctgaggcaggtggatcacgaggtcaggagttcaagacctgcctggccaaaatggtgaaacccccatctgtactaaaaatacaaaaattagctgggcatggtgatgggtgcctgtaatcccagctactcgggaggctgaggcagagaattgcttgaacccaggaggcagaggttgcagtgagccaagatcgtgccactgcactccagcctgggtgacagagcaagactccatctcaaaaaaaaaaaaaaaaaaaagttcccacggtgctgccgagcctgtgattggcagaggcattgtttattcgttcaaggttttttgttaagggacccggtgagtatcaactactaggcagttctcacttctgctcacttctgggctcacttaagcctaccagcagccctgaaggctgttaaccaccctttagagcttagagagtcgaagaggcaggggccaggtcctaaagaaaggcacactgtccccagagcctggggcgcgatgccacccgccccccccccccccgcccaggcgtacccccccttaccccgccccccacccgctcgccgcgcccagcccatctggcgccgctctgcccctgctgagtaatcctttcccgagccacgtggccgtgtttttcctgctgagtcacggtcccgaggtctattttcgctaagtcaccgccccgagatctgttttcgctgagtcacggtcccggtgtctgttttcgctgagtcacggtctagagatttgttttcctcagagttccagctgctccaggtttaatcccctggggcaaagtccggactgtccggctggagtctggagtcgggacatgcctcagccagcacgtcctcggcctcgtctggggcctgaatcctagggaagccatagcagctcctccacccttcctctcactcctcctctagcctcttgctactccccgcaccactgttttagggaacctctatctcccgacggcctgccacgggccaggcgctgtgctgggggcttcacactttaaatcgctgttgagcggggcgcgggggcgctgcaacctaaaggtgggagctactcaaatggaggggcatctgttaaaatggccggcctgtcattttcaaaaacttcaaggccgggcgcggtggctcacgcctgtaatcccagcactttgggaggccgaggcgggcggatcacgaggtcaggagatcgagatcatcttgtctaacacggtgaaacttcatctctactaaaaatagaaaaaattagccgggcgtggtggcgggcgcctgtaatcccagctactcaggaggctgaggcaggagaatggcatgaacccgggaggcggagcttgcagtgagccgaaatcgcgccactgcagtccggcctgggcgaaagagcaagactccgcctcaaaaaaaaaaaaaaaaaaaaacttcaaaggctgaggaacccaaagaggcaggacaagtgaatgcaatgcaacctcttgggctggaacctggactggtaaaacggctaaagaggaggttattggggcaataggggacatttgaatataggctttatattgaaggagttcaggatatgccacccaaaatgtgccactttggattaaggatcattattattattattattattattttgagacagggtctctgtcacccaagctgcagtgcagtggcacaatctcggctcactgcaacctctgcctcctaggttcaagcgattctcgtgcctc.

4. Generation of Stable Cell Lines

In order to generate cells that stably express luciferase expressionvectors that lack a mammalian antibiotic selection cassette, HEK293cells were co-transfected with either pHOGL3/4.5+220 (Deshane et al,2010) or the Triple Mutant construct (Liby, Hock et al, 2005; Hock etal, 2007) and pcDNA3.1 Zeocin using Lipofectamine 2000. Cells werecultured in Zeocin (400 ug/ml; Invitrogen) for selection. Individualclones were sorted by flow cytometry and plated into a 96-well plate ata density of one cell per well. Clones were maintained and expanded incomplete media (DMEM/10% FBS/1× antibiotic-antimycotic) supplementedwith 100 ug/ml Zeocin, and incubated at 37° C. in 5% carbon dioxide.Incorporation of the Luciferase expression vectors was validated byassaying for luciferase.

5. High Throughput Screen (HTS)

A library of over 150,000 compounds, as well as a library of over 4,000FDA approved compounds, were used in the HTS assay. To identify falsepositive hits, a secondary screen was employed using a similar stablecell line in which three point mutations in the promoter region renderit inactive. This led to the identification of approximately 800compounds that induce HO-1 and have desirable chemical structures.Compounds exhibiting E_(max)≥70% of 5 μM hemin and EC₅₀<10 μM wereassayed for endogenous HO-1 expression in HEK-293 cells. The In-CellWestern assay was optimized to screen for endogenous HO-1 in a highthroughput platform, and results were validated by Western blot,real-time PCR, and enzyme activity assays. Additional RNA sequencingstudies highlighted a role for the transcription factor Nrf2 and othertargets in HO-1 induction by several small molecules. Furthermore, theability of these compounds to inhibit cisplatin-induced cytotoxicity inHEK-293 cells was demonstrated.

6. Chemistry Experimentals

All reactions were carried out in an oven-dried glassware under argonatmosphere using standard gas-tight syringe, cannula, and septa. Thereaction temperatures were measured externally. Stirring was achievedwith oven dried magnetic bars. All the reactions were done in anhydroussolvents (CH₂Cl₂, THF, MeOH) purchased from Sigma-Aldrich. Allcommercially purchased reagents were used without purification. Thereactions were monitored by thin-layer chromatography (TLC) on apre-coated silica gel (60 F254) glass plates from EMD Millipore andvisualized using UV light (254 nm). Purification of the compounds wasperformed on Teledyne-ISCO Combiflash Rf 200 purification systemby usingRedisep Rf® normal phase silica gel columns 230-400 mesh. ESI-MS spectrawere recorded on a BioTof-2 time-of-flight mass spectrometer. Proton NMRspectra were recorded on a Varian Unity 400 NMR spectrometer operatingat 400 MHz calibrated to the solvent peak and TMS peak. The chemicalformula and Exact Mass for target compounds were determined from the(M+H)⁺ by high resolution mass spectroscopy using an Agilent 6210Electrospray Time of Flight.

a. Representative Synthesis of Compound 1

All exemplary compounds were prepared as illustrated above and describedmore fully below for compound no. 1.

Briefly, a solution of 4-amino-2,6-difluoro-phenyol (115 mg, 0.79 mmol)and 3-bromo-1-phenyl-pyrrole-2,5-dione (see Li, et al. “A mild andselective protecting and reversed modification of thiols,” TetrahedronLetters 57(24): 2660-2663) (200 mg, 0.79 mmol) in Ethanol (10 mL) washeated at 80° C. for overnight. Solvent was removed from the reactionmixture and the resultant residue was purified on Teledyne IscoCombiflash® Rf purification machine to afford3-(3,5-difluoro-4-hydroxy-anilino)-1-phenyl-pyrrole-2,5-dione, 1, as ayellow solid in 29% yield (HPLC purity: 96.5%). ESI-MS m/z: 317.1. ¹HNMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 9.82 (s, 1H), 7.52-7.43 (m,2H), 7.40-7.30 (m, 3H), 7.21-7.08 (m, 2H), 5.88 (d, J=0.5 Hz, 1H). HRMScalcd for [C₁₆H₁₀F₂N₂O₃+H]⁺: 317.0732, Found 317.0728.

7. Evaluation of Biaryl Aminomaleimides

A list of compounds evaluated is shown in Table 1 below.

TABLE 1 HPLC EC₅₀ Purity No. Structure (μM) E_(max) (%) HRMS  1 40109

3.08 90.6 96.5 Calculated: 316.0659, Found: 316.0654  2 41160

1.81 38.1 100 Calculated: 280.0848, Found: 280.0844  3 41573

1.86 56.4 96.6 Calculated: 298.0754, Found: 298.0755  4 41574

1.78 38.9 98.9 Calculated: 298.0754, Found: 298.0748  5 41575

31.3 72.8 99.6 Calculated: 348.0068, Found: 348.0056  6 41576

1.74 20.4 99.1 Calculated: 314.0458, Found: 314.0458  7 41577

>50 99.1 Calculated: 314.0458, Found: 314.04478  8 41578

5.49 41.7 98.2 Calculated: 316.0659, Found: 316.0653  9 41579

1.69 33.7 96.4 Calculated: 332.0364, Found: 332.0358 10 41768

>50 98.9 Calculated: 316.0659, Found: 316.0655 11 41773

>50 94.1 Calculated: 348.0722, Found: 348.0720 12 41775

7.55 39.3 99.5 Calculated: 308.1161, Found: 308.1157 13 42256

>50 99.4 Calculated: 331.0957, Found: 331.0960 14 42255

2.97 49.1 98.2 Calculated: 316.0659, Found: 316.0656 15 41223

>50 94.3 Calculated: 316.0659, Found: 316.0655 16 41224

>50 99.7 Calculated: 348.0068, Found: 348.0063 17 41226

11.96 54.4 99.6 Calculated: 316.0659, Found: 316.0656 18 41938

>50 95.0 Calculated: 316.0659, Found: 316.0664 19 41585

>50 99.1 Calculated: 332.0364, Found: 332.0362 20 41766

>50 96.6 Calculated: 348.0068, Found: 348.0066 21 41164

>50 100 Calculated: 318.0616, Found: 318.0612 22 41167

>50 97.4 Calculated: 349.1426, Found: 349.1426 23 40102

>50 98.5 Calculated: 330.0816, Found: 330.0812 24 41163

>50 98.5 Calculated: 308.0797, Found: 308.0791 25 44030

>50 96.5 Calculated: 279.1008, Found: 279.1005 26 41572

4.21 80.7 94.6 Calculated: 334.0565, Found: 334.0561 27 43508

>50 72.6 92.9 Calculated: 352.0471, Found: 352.0472 28 43509

16.88 31.3 100 Calculated: 370.0377, Found: 370.0376 29 43510

3.34 109.5 94.4 Calculated: 350.0270, Found: 350.0270 30 43512

2.91 110.8 94.0 Calculated: 346.0765, Found: 346.0765 31 43513

2.31 64.01 95.9 Calculated: 401.0559 [M + H], Found: 401.0559 32 43517

12.87 38.1 98.3 Calculated: 360.0558, Found: 360.0555 33 43520

2.08 28.36 94.9 Calculated: 406.0976, Found: 406.0977 34 43519

>50 28.27 98.5 Calculated: 380.0375, Found: 380.0374 35 43718

2.10 96.8 99.0 Calculated: 330.0816, Found: 330.0814 36 43514

0.89 52.5 94.4 Calculated: 358.1129, Found: 358.1132 37 43555

1.56 57.22 96.9 Calculated: 344.0972, Found: 344.0970 38 43515

2.29 57.0 98.4 Calculated: 344.0972, Found: 344.0974 39 43727

4.32 94.9 95.9 Calculated: 384.0533, Found: 384.0534 40 43518

>50 98.1 Calculated: 341.0612, Found: 341.0609 41 43731

11.49 70.4 98.9 Calculated: 399.1394, Found: 399.1388 42 43720

>50 100 Calculated: 383.0718, Found: 383.0714 43 43721

1.03 67.5 93.4 Calculated: 330.0816, Found: 330.0813 44 43725

19.10 99.6 91.5 Calculated: 374.0714, Found: 374.0705 45 43726

36.15 141.3 99.3 Calculated: 366.0816, Found: 366.0810 46 43722

0.43 68.5 96.4 Calculated: 344.0972, Found: 344.0969 47 43728

19.65 91.1 98.0 Calculated: 384.0533, Found: 384.0533 48 43736

13.73 82.9 98.2 Calculated: 334.0565, Found: 334.0560 49 43724

8.37 69.6 94.6 Calculated: 382.0577, Found: 382.0571 50 43735

15.27 75.2 98.4 Calculated: 332.0609, Found: 332.0607 51 43719

15.39 62.4 98.3 Calculated: 359.0718, Found: 359.0717 52 43730

13.99 53.1 95.9 Calculated: 364.0671, Found: 364.0665 53 44025

3.35 94.1 97.4 Calculated 359.1081, Found: 359.1079 54 43860

19.99 54.9 98.4 Calculated: 346.0765, Found: 346.0761 55 43863

2.27 93.28 96.3 Calculated: 382.0577, Found: 382.0571 56 43857

8.39 36.1 95.2 Calculated: 371.0718, Found: 371.0713 57 44028

5.67 98.7 94.2 Calculated: 364.0671, Found: 364.0667 58 43862

1.73 53.3 97.7 Calculated: 372.1285, Found: 372.1280 59 44027

9.22 43.9 100 Calculated: 399.0489, Found: 399.0488 60 44026

22.23 66.9 96.2 Calculated: 401.1187, Found: 401.1188 61 43864

3.77 33.4 98.4 Calculated: 408.0922, Found: 408.0915 62 44024

2.75 34.6 95.7 Calculated: 392.0972, Found: 392.0968 63 43858

3.19 30.0 98.0 Calculated: 334.0565, Found: 334.0562 64 43859

3.33 23.9 98.6 Calculated: 384.0533, Found: 384.0532 65 43861

15.59 42.8 94.7 Calculated: 374.0714, Found: 374.0707 66 44029

>50 91.6 Calculated: 341.0612, Found: 341.0608 67 43511

>50 25.6 97.5 Calculated: 322.1129, Found: 322.1131 68 43521

>50 95.3 Calculated: 280.0659, Found: 280.0660 69 42542

16.7 105 97.7 Calculated: 332.0609, Found: 332.0604 70 42540

>50 99.0 Calculated: 316.0659, Found: 316.0650

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound having a structure represented by aformula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; and wherein each of R^(3a),R^(3b), R^(3c), and R^(3d) is independently selected from hydrogen,halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4aminoalkyl, provided that when one or two of R^(1a), R^(1b), R^(1c),R^(1d), and R^(1e) is —OH or C1-C4 alkoxy and the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are hydrogen, then at leasttwo of R^(3a), R^(3b), R^(3c), and R^(3d) are non-hydrogen groups,provided that when one or two of R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) is —OH or C1-C4 alkoxy and at least one of the remaining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups is a different non-hydrogengroup, then at least one of R^(3a), R^(3b), R^(3c), and R^(3d) arenon-hydrogen groups, and provided that when one of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is C1-C4 hydroxyalkyl, then at least one ofR^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(3a), R^(3b), R^(3c), andR^(3d) is a non-hydrogen group, or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein n is
 0. 3. The compound ofclaim 1, wherein each of R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) isindependently selected from hydrogen, halogen, —CN, —NH₂, —OH, —NO₂,C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰, —CO₂R¹¹, Cy¹,and —OCy¹.
 4. The compound of claim 1, wherein each of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is independently selected from hydrogen,halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, and C1-C4alkoxy.
 5. The compound of claim 1, wherein each of R^(1a), R^(1b),R^(1c), R^(1d), and R^(1e) is independently selected from hydrogen andhalogen.
 6. The compound of claim 1, wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
 7. The compound ofclaim 1, wherein two adjoining R^(1a), R^(1b), R^(1c), R^(1d), andR^(1e) groups are covalently bonded and, together with the intermediateatoms, comprise a 5- or 6-membered cycloalkyl, a 5- or 6-memberedheterocycloalkyl, a 6-membered aryl, or a 5- or 6-membered heteroaryl,and is unsubstituted.
 8. The compound of claim 1, wherein each ofR^(3a), R^(3b), R^(3c), and R^(3d) is independently selected fromhydrogen and halogen.
 9. The compound of claim 1, wherein each of R^(3a)and R^(3d) is hydrogen and each of R^(3b) and R^(3c) is halogen.
 10. Thecompound of claim 1, wherein the compound has a structure represented bya formula:


11. The compound of claim 1, wherein the compound has a structurerepresented by a formula:


12. The compound of claim 1, wherein the compound has a structurerepresented by a formula:


13. The compound of claim 1, wherein the compound is not:


14. The compound of claim 1, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 15. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundhaving a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 16. A method for treating a disorder associated withheme oxygenase-1 (HO-1) signaling dysfunction in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound having a structure represented by a formula:

wherein n is 0, 1, or 2; wherein each of R^(1a), R^(1b), R^(1c), R^(1d),and R^(1e) is independently selected from hydrogen, halogen, —CN, —NH₂,—OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, —C(O)R¹⁰,—CO₂R¹¹, Cy¹, and —OCy¹; wherein R¹⁰, when present, is selected fromhydrogen, —NH₂, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R¹¹, whenpresent, is selected from hydrogen and C1-C4 alkyl; and wherein Cy¹ isselected from C6 aryl, C2-C5 heteroaryl, C3-C6 cycloalkyl, and C2-C5heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4 alkyl,C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and C1-C4 aminoalkyl; or wherein two adjoining R^(1a),R^(1b), R^(1c), R^(1d), and R^(1e) groups are covalently bonded and,together with the intermediate atoms, comprise a 5- or 6-memberedcycloalkyl, a 5- or 6-membered heterocycloalkyl, a 6-membered aryl, or a5- or 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3groups independently selected from halogen, —CN, —NH₂, —OH, —NO₂, C1-C4alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; wherein R² isselected from hydrogen and C1-C4 alkyl; wherein each of R^(3a), R^(3b),R^(3c), and R^(3d) is independently selected from hydrogen, halogen,—CN, —NH₂, —OH, —NO₂, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; andwherein R⁴ is selected from hydrogen, halogen, and C1-C4 alkyl, or apharmaceutically acceptable salt thereof, thereby treating the disorderin the subject.
 17. The method of claim 16, wherein the disorderassociated with HO-1 signaling dysfunction is a kidney disease.
 18. Themethod of claim 17, wherein the kidney disease is chronic kidney diseaseor acute kidney injury (AKI).
 19. The method of claim 16, wherein thesubject is a mammal.
 20. The method of claim 16, wherein the subject hasbeen diagnosed with a need for treatment of the disorder prior to theadministering step.